Scientists at Joslin Diabetes Center have identified a key mechanism of action for the TOR (target of rapamycin) protein kinase, a critical regulator of cell growth which plays a major role in illness and aging. This finding not only illuminates the physiology of aging but could lead to new treatments to increase lifespan and control age-related conditions, such as cancer, type 2 diabetes, and neurodegeneration.
Over the past decade, studies have shown that inhibiting TOR activity, which promotes cell growth by regulating protein synthesis, increases lifespan in a variety of species including flies and mice; in recent years research has focused on uncovering the precise mechanisms underlying this effect. The Joslin study, published in the May 2 issue of Cell Metabolism, reports that TOR has a direct impact on two master gene regulator proteins -- SKN-1 and DAF-16 -which control genes that protect against environmental, metabolic and proteotoxic stress. The TOR kinase acts in two signaling pathways, TORC1 and TORC2. When TORC1 is inhibited, SKN-1 and DAF-16 are mobilized, leading to activation of protective genes that increase stress resistance and longevity. This new finding was demonstrated in experiments with C. elegans, a microscopic worm used as a model organism, but activation of protective genes was also observed in mice. Most findings in C. elegans have turned out to be applicable to mice and humans.
"We uncovered a critical mechanism in the relationship between TOR and aging and disease. There is a homeostatic relationship between protein synthesis and stress defenses: when protein synthesis is reduced, stress defenses increase," says lead author T. Keith Blackwell, MD, PhD, co-head of the Joslin Islet Cell & Regenerative Biology Section and Professor of Pathology at Harvard Medical School. The Blackwell lab studies the aging process and how it is influenced by insulin and other metabolic regulatory mechanisms.
TOR activity, which is essential for early development but can lead to age-related decline, is implicated in a variety of chronic diseases, including diabetes, cardiovascular disease, cancer and neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. In diabetes, TOR has both positive and negative effects: It promotes beta cell growth and insulin production but inappropriate TORC1 activity leads to insulin resistance and beta cell demise, as well as fat accumulation. At the same time, insufficient TORC2 activity can lead to insulin resistance.
The new results on TOR and SKN-1 suggest that SKN-1 might have a positive effects in Type 2 diabetes: "Turning on this pathway could be important in defending against the effects of high glucose, and promoting beta cell health" says Blackwell.
In the study, TOR activity was inhibited by genetic interference and the TOR-inhibitor rapamycin, a naturally occurring compound which is used as an immunosuppressant in organ transplants, and has been shown to increase lifespan in mice. Using rapamycin or related drugs to treat diseases affected by TOR has been a subject of intense interest among scientists and clinicians. The study found that rapamycin inhibits both TORC1 and TORC2, which will interest scientists investigating rapamycin as a pharmaceutical. "We need to increase understanding of rapamycin and its effects on TOR activity to determine how targeting TOR or processes it controls can help treat diseases that involve TOR and derangement of metabolism. We also need to look at therapies that work on TORC1 and TORC2 independently," said Blackwell. However, one caveat with TOR inhibition is that the kinase plays such a central role in the basic physiology of growing and dividing cells. The new results suggest that in some situations we might want to bypass TOR itself, and directly harness beneficial processes that are controlled by SKN-1 or DAF-16.
Future research will focus on gaining a deeper understanding of how TOR acts on beneficial defense pathways and affects aging and disease. "In science, we are always looking for ways to interfere with mechanisms that promote aging and disease in ways that are beneficial to people," says Blackwell.
The study was supported by supported by grants from the National Institutes of Health (National Institute of General Medical Sciences) and the Ellison Medical Foundation.
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